Recent studies have revealed an unexpected plasticity of afferent pain pathways following neuropathic or inflammatory injury, and concomitant changes in the efficacy of opioid analgesics. Previous investigations of the effects of injury limited their examination to neurons in the periphery and the spinal cord. Consequently, very little is known about the effects of injury at the supraspinal level and, in particular, about the effects of inflammatory nociception on the pain modulatory pathways that originate in the pons or medulla. Neurons in NRM and NGCp alpha of the ventromedial medulla that project to the spinal cord comprise one of the important, common efferent pathways for the modulation of nociception, and are also implicated in the production of antinociception by opioid receptor agonists. Recent studies in this laboratory indicate that the antinociceptive effects of DAMGO, a mu opioid receptor agonist, are enhanced after microinjection in the NRM or NGCp alpha of rats with monoarthritis induced by intraplantar injection of CFA. However, the mechanism for this enhancement is unknown. This application proposes to use neuroanatomical and molecular neuroanatomical techniques to identify the mechanisms responsible for this enhancement. Its specific aims are to: Use in situ hybridization histochemistry to identify alterations in the expression of mRNA for the endogenous opioid peptides and their receptors as a function of time after injury. Use immunocytochemistry to identify corresponding alterations in the number and distribution of neurons immunoreactive for these peptides and their receptors. These experiments will provide new insights into the effects of inflammatory nociception on brainstem neurons that comprise an important efferent pathway for the modulation of nociception and a key site of action for opioid analgesics. Moreover, the findings of these experiments will be strengthened by our ability to relate these alterations to the results of ongoing pharmacological investigations of the effects of opioid receptor agonists and antagonists in the ventromedial medulla after inflammatory injury.